Advances in human genomic sequencing are revealing disease-causing mutations at younger ages, allowing improved patient management through earlier disease prediction. However in some diseases, such as the rare, recessive lysosomal storage disorder Niemann-Pick disease, type C1 (NPC1; MIM #257220), accurate prognostic information is difficult because NPC1 disease is extremely heterogeneous in the timing of clinical presentation (early infancy to adulthood), is associated with a wide spectrum of causative NPC1 (Gene ID 4864) mutations, and shows little concordance between the predicted consequences of NPC1 gene mutation on protein function with time of onset or severity of the disease [1,2].
Niemann-Pick disease (NPD) refers to a group of fatal inherited metabolic disorders that are associated with defects in the metabolism of sphingolipids. NPC1 encodes a trans-membrane protein involved in intracellular cholesterol trafficking, and its mutation causes intracellular accumulation of unesterified cholesterol in late endosomal/lysosomal structures and marked accumulation of glycosphingolipids, especially in neuronal tissue. The NPC1 protein mediates intracellular cholesterol trafficking via binding of cholesterol to its N-terminal domain. Clinical signs and symptoms associated with Niemann-Pick disease, type C include defects in ambulation, cognition, eye movement, fine motor, hearing, memory, seizures, speech, and swallowing. Consequently, NPC1 disease presents with hepatosplenomegaly and neurological degeneration that leads to premature death. Current diagnosis of NPC1 involves clinical assessments as well as analysis of genetic and biochemical parameters to predict time of onset of neurological symptoms, and highlights the need for new, more informative assays for NPC1 disease. Moreover, the lifespan of subjects with NPD is related to the age of onset. At present, it is not possible to predict the age of NPD onset. Methods for predicting the age of onset are urgently required.